Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients

• Published in: Thrombosis and haemostasis Vol. 97; no. 5; p. 788
• Main Authors: Hu, Genlin, Guo, Delan, Key, Nigel S, Conti-Fine, Bianca M
• Format: Journal Article
• Language: English
• Published: Germany 01.05.2007
• Subjects: Adult; Aged; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cell Proliferation; Cytokines - biosynthesis; Factor VIII - immunology; Female; Hemophilia A - blood; Hemophilia A - immunology; Humans; In Vitro Techniques; Interferon-gamma - biosynthesis; Interleukin-4 - biosynthesis; Lymphocyte Activation; Male; Middle Aged; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - immunology; Th1 Cells - immunology; Th2 Cells - immunology; Transforming Growth Factor beta1 - biosynthesis
• ISSN: 0340-6245
• DOI: 10.1160/TH06-09-0519

Haemophilia A patients treated with human factor VIII (fVIII) may develop antibody (Ab) inhibitors to fVIII. FVIII-specific CD4(+) T cells are common in haemophilia A patients, but also in healthy subjects who do not have a sustained anti-fVIII Ab response. Here, we examined the fVIII-induced IFN gamma-, IL-4- and TGF-beta1-producing CD4(+) T blasts by culturing peripheral blood mononuclear cells (PBMC) from controls and patients with recombinant fVIII. FVIII exposure significantly increased IFN gamma- and IL-4-, but not TGF-beta1-producing CD4(+) T blasts in patients with inhibitors. Patients without inhibitors had fVIII-induced IFN gamma- and TGF-beta1-, but not IL-4-producing CD4(+) T blasts. Controls did not have IL-4-producing CD4(+) T blasts. However, controls whose PMBC proliferated in response to fVIII had fVIII-induced CD4(+) T blasts that produced IFN-gamma, the number of which correlated with the intensity of the proliferative response to fVIII of their PMBC, whereas controls whose PMBC did not proliferate to fVIII had predominantly fVIII-induced CD4(+) T blasts that produced TGF-beta1. The presence in controls and patients without inhibitors of fVIII-induced IFN-gamma-producing CD4(+) T cells, but not IL-4-producing CD4(+) T cells, which are abundant in inhibitor patients, suggests a role of Th1 cells in initiating the immune response to fVIII, and of Th2 cells in the development of strong inhibitor production. The polarized high ratios of Th3/Th1 and Th3/Th2 in controls and patients without inhibitors suggest that a preponderance ofTh3 cells in the response to fVIII may help to maintain tolerance to fVIII.